Advances in antibody-conjugating drugs in prostate cancer: applications and challenges

Overcoming Challenges in the Development of Anticancer ADCs

With more than 230,000 new cases each year in the United States, prostate cancer is the most common cancer diagnosed among American men [(1)][1] . Prostate cancer is expected to account for nearly 30,000 deaths in the United States in 2004 and consequently represents the second most common cause of

In the worldwide male population, prostate cancer has the most frequent malignancy; out of all the cancer-related causes of deaths, it is also one of the most common. With the advance of new therapies of androgen receptor pathway inhibitors, patient survival rates have improved significantly. There are still tremendous unmet needs, however, for the patients with treat-refractory metastatic castration-resistant prostate cancer (mCRPC). LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. Previous studies with immunohistochemical (IHC) analysis showed that LIV-1 is expressed by estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) and ER-/PR-/Her2- (triple-negative) breast cancers. These studies also showed that in healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). The broad expression of LIV-1 in prostate and breast cancer tumors in combination with the limited expression in vital organs makes LIV-1 an excellent target for an antibody-drug conjugate (ADC). We generated an ADC, BRY812, consisting of a humanized anti-LIV-1 mAb conjugated to monomethyl auristatin E (MMAE), via a novel conjugation method that prevents MMAE from coming off of the antibody during the circulation. The PK studies in rat and monkey showed that the free MMAE released from ADC is 1 to 2 log lower compared with approved ADCs prepared by the standard conjugation method. Low free MMAE concentration significantly lowers the risk of off target toxicity by the ADC. In vitro and in vivo studies demonstrated the antitumor activity of BRY812 for the treatment of prostate and ER+ and triple-negative breast cancers with a better safety profile and a larger therapeutic window. The humanized LIV-1 ADC, BRY812 is currently in preclinical toxicity studies and will advance to First-in-Human trials in April, 2023. Citation Format: Xiaobei Zhao, Gang Chen. Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B075.

Novel therapies for advanced prostate cancer: have we have widened the goal posts too far?

145 Background: Black men represent only 6.7% of patients enrolled in therapeutic prostate cancer (PCa) clinical trials. Low levels of knowledge and lack of awareness are the most substantial patient-specific barriers to participation. Our aim was to develop and implement a personalized education tool effectively bridging the gap between Black patients with PCa and healthcare providers while improving attitudes regarding clinical trial participation. Methods: Leveraging a novel collaboration between the Prostate Health Education Network (PHEN), a well-established advocacy group for Black men with PCa, and Memorial Sloan Kettering Cancer Center (MSKCC), PHEN-Clinical Trials Learning Sessions (CTLS) were developed. Black PCa patients were recruited from MSKCC and the PHEN network to participate in PHEN-CTLS via telephone and radio advertisement. Pre- and post-CTLS surveys collected demographic/clinical data, patient satisfaction scores as well as knowledge and attitudes regarding clinical research. Results: PHEN-CTLS were successfully developed as 90-minute, interactive Zoom webinars focusing on general clinical research topics and PCa specific material highlighting MSKCC clinical trials and PROMISE, a decentralized PCa genetic registry. A total of 78 men attended the MSKCC affiliated PHEN-CTLS, performed on 2 separate dates. Due to suboptimal survey completion during session one, the following data analysis is limited to the 22 participants who returned both surveys during session two. Demographic and disease characteristics were as follows: 55% age 61 – 70 years, 59% married, $50,000 – $100,000 median annual income, 68% college or post-graduate educated, 48% with a known family history of PCa, 50% diagnosed more than 10 years prior, and 63% localized disease state. All men who never participated in a clinical trial reported the primary reason for not doing so being that “no one spoke to them about the option”. Clinical trial knowledge and perceptions improved in response to PHEN-CTLS: 50% vs 83% (and 45% vs 81%) “agree/strongly agree” informed of potential benefits (and risks) of clinical trial participation and 64% vs 100% “agree/strongly agree” willing to participate in a clinical trial (pre- vs post-CTLS survey). Conclusions: Combining expert educational content development, grassroots patient advocacy, and academic research excellence, PHEN-CTLS is the first education program of its kind. The intervention is feasible, and an effective means to improve patient knowledge of, attitudes toward, and a willingness to participate in clinical trials. Next steps in development will include, expanding participant numbers and geographic diversity, broadening survey questions and evaluating effect on PROMISE and PCa clinical trial enrollment.

An Antibody-Drug Conjugate (ADC) is a monoclonal antibody targeted against an antigen on the cancer cell surface and is conjugated to a cytotoxic drug (payload) via a chemical linker. To date no ADCs were clinically approved for prostate cancer (PCa) therapy due to a lack of efficacy and systemic toxicity. Rational design of ADCs and development of combinatorial ADC-based approaches may enhance the therapeutic window for the effective treatment of PCa. In this work we (1) analyzed the distribution of ADC target antigens in advanced PCa and (2) explored synergistic interactions between ADC payloads to propose new combination therapy with improved efficacy and cancer specificity. Multiplexed immunofluorescent staining of lethal metastatic castration-resistant prostate cancers (mCRPCs) have shown that majority of androgen receptor regulated (AR+) mCRPCs were double-positive for B7-H3 & STEAP1 or B7-H3 & PSMA or PSMA & STEAP1, nominating these antigen pairs as targets for dual ADC therapy. To identify synergistic ADC payloads, we have designed a custom drug screen that included 23 cytotoxic agents from 3 major payload classes and 78 drug combinations. Validation of screening results in prostate cancer cell lines have demonstrated that Bcl-xl inhibitor A-1331852 interacts synergistically with either DNA-damaging payload tested in the screen, and that isolated loss of p53 can induce resistance to proposed combinations. To introduce these synergistic payloads into ADC approach we obtained 3 genotoxic conjugates (B7-H3 - seco-DUBA, PSMA – SG3249, and STEAP1 – DXd) and tested them as single agents and combined with systemic A-1331852 in p53-proficient and p53-deficient prostate cancer cells. Co-administration of B7-H3 – seco-DUBA ADC with A-1331852 was also tried in mCRPC xenografts with different p53 statuses. Although faster and greater responses to ADC/payload combinations were observed in models with intact p53, addition of systemic A-1331852 improved the efficacy of DNA-damaging ADCs in all models tested in vitro and in vivo. These findings suggest that concurrent use of an ADC bearing DNA-damaging payload with an ADC bearing Bcl-xl inhibitor is a promising therapeutic strategy for the treatment of mCRPC. In conclusion, this work addresses challenges associated with ADC monotherapy in mCRPC and explores the potential of rational ADC combinations. We nominate B7-H3, PSMA, and STEAP1 as targets for ADC co-targeting, and we propose to use DNA-damaging agents and Bcl-xl inhibitor A-1331852 as payloads for dual ADC therapy. Because the prototypes of such ADCs have already demonstrated safety in early phase human studies, the data generated in this work enables near-term clinical development of new agents for mCRPC therapy. To our knowledge, described study is the first to propose the use of ADC combinations for the treatment of mCRPCs. This work was supported by PCF Young Investigator Award to GS Citation Format: Galina Semenova, Ilsa Coleman, Roman Gulati, Colm Morrissey, Michael Haffner, Peter S Nelson, John K Lee. Experimental antibody-drug conjugate combinations for advanced prostate cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B112.

Breast cancer remains the most prevalent malignancy among women globally, presenting significant challenges in therapeutic strategies due to tumor heterogeneity, drug resistance, and adverse side effects. Recent advances in targeted therapies, particularly antibody-drug conjugates (ADCs), have shown promise in addressing these challenges by selectively targeting tumor cells while sparing normal tissues. This study provides a comprehensive analysis of two innovative ADCs targeting HER2 and Trop-2, which are critical markers in various breast cancer subtypes. These conjugates combine potent cytotoxic drugs with specific antibodies, leveraging the antigens' differential expression to enhance therapeutic efficacy and reduce systemic toxicity. Our comparative analysis highlights the clinical applications, efficacy, and safety profiles of these ADCs, drawing on data from recent clinical trials. In addition, the paper discusses the potential of these ADCs in treating other types of cancers where HER2 and Trop-2 are expressed, as well as the toxicity risks associated with targeting these antigens in normal cells. Additionally, the paper discusses novel synthetic drugs that show potential in preclinical models, focusing on their mechanisms of action and therapeutic advantages over traditional chemotherapy. The findings underscore the transformative impact of targeted ADCs in breast cancer treatment, noting significant advancements in patient outcomes and management of side effects. However, ongoing issues such as resistance mechanisms and long-term safety remain challenges. The conclusion offers a forward-looking perspective on potential improvements and the future trajectory of ADC research. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics, with particular attention to their broader applications and associated risks.

We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ongoing trials targeting both metastatic and early-stage patients. Notably, we explore trials incorporating investigational ADCs into early management strategies, addressing the unique challenges of biomarker identification, target toxicity, and cost-effectiveness. By summarizing the current landscape of FDA-approved and investigational ADCs, this study highlights the evolving nature of BC treatment. Preliminary findings from ongoing trials suggest that early integration of ADCs can lead to significant improvements in disease-free survival, reinforcing their role in personalized medicine. As research advances, ADCs are likely to become a cornerstone of breast cancer treatment, providing new hope for better patient outcomes.

BackgroundBreast cancer (BC) remains the most commonly malignancy among women worldwide. Although early-stage BC typically presents with curative possibilities, advanced-stage disease, especially with metastasis, is significantly limited in terms of effective therapeutic interventions, thereby establishing it as the second leading cause of cancer-related deaths in women. Antibody–Drug Conjugates (ADCs) establish a groundbreaking class of anti-neoplastic agents characterized by high specificity and targeting precision. These agents have been significant in reshaping the therapeutic approach to breast cancer, especially those subtypes with overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2). Comprising monoclonal antibodies, cytotoxic payloads, and conjugative linkers, ADCs function by specifically targeting antigens on cancer cells, thereby facilitating the intracellular delivery of the toxic payload. The present investigation endeavors to synthesize existing primary research outcomes through rigorous bibliometric and data analytical approaches, thereby elucidating the current research landscape, delineating research foci, and identifying potential avenues for future innovation.MethodsFor bibliometric analysis, a comprehensive data set comprising 2181 entries related to ADCs in breast cancer was retrieved from the Web of Science Core Collection (WoSCC) spanning the years 1999 to 2023. This data was further filtered from the Science Citation Index Expanded (SCI-Expanded). Analysis software tools such as CiteSpace and VOSviewer were employed for multifaceted analyses such as trends of publications, contributions of countries, and burst analytics. In the dimension of clinical trials, we interrogated databases including ClinicalTrials.gov (https://www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (https://trialsearch.who.int). A total of 239 clinical trials were initially sourced, among which, 175 were from ClinicalTrials.gov and 64 from ICTRP. After repetitive and correlation-based screening, 119 trials specifically addressing ADC therapeutic strategies in breast cancer were included. Analytical algorithms were executed using Microsoft-based software to evaluate treatment paradigms, emergent research themes, and progress.ResultsOur investigations signify a growing trend of research on ADCs, with consistent advancements in scientific achievements. The analysis revealed that variables such as economic stratification of nations, healthcare investment paradigms, and disease incidence rates serve as significant determinants in shaping research output. Geographically, the United States emerged as the predominant contributor to the research corpus (36.56%), closely followed by China (21.33%). The underpinning of research accomplishments was found to be significantly bolstered by advancements in molecular biology, immunology, and genetic research. Moreover, the advent of nuclear magnetic resonance diagnostic modalities has contributed saliently to the diagnostic and therapeutic management of breast cancer.ConclusionOur study provides a comprehensive overview of the ADC research landscape through rigorous bibliometric and clinical trial evaluations. At present, the ADC arena has witnessed the successful development and FDA approval of 14 distinct agents, substantially improving the clinical outcomes for a broad spectrum of oncological patients. Future research imperatives may include the exploration of ADCs targeting mutated oncoproteins, dual-specificity ADCs, combination payload strategies, peptide-drug conjugates (PDCs), and non-internalizing ADC modalities. With sustained academic and clinical focus, the ADC domain is poised for transformative advancements in targeted therapeutics across a variety of malignancies.

25 Background: It is known that ethnic and racial inequality in participation in oncology clinical trial is a contemporary problem. Efforts have been made by NCI and FDA to address cancer disparities as per new policies placed in 2017. Despite these efforts, there are still disparities in cancer treatment and clinical trial participation. There is paucity of data in participation of minorities in the post COVID-19 era of the FDA approved agents in Prostate Cancer. Methods: From 2020-2024, a total of 4,744 patients participated in the seven clinical trials (MAGNITUDE, TALAPRO-2, VISION, PROPEL, ARASENS, HERO, PROfound and TRITON3) that led to FDA approval of new agents or indications to treat patients with prostate cancer. All clinical trials were industry-sponsored. We assessed and tabulated the reporting of racial demographics within these trials employing chi-square statistics and machine learning algorithms to compare participation rates among White, Black, Asian and Hispanic patients against SEER data on prostate cancer incidence. Results: Among the eight trials, five (ARASENS, MAGNITUDE, PROPEL, TALAPRO, TRITON-3) reported racial data in White, Asian and Black participants, but only one reported data on Hispanics (MAGNITUDE). Our analysis revealed that in the five trials providing racial data, 68% were White indicating statistically significant overrepresentation (p<0.001), Black participation was only 3% signifying statistically significant underrepresentation with (p<0.0001). In the only trial with data in Hispanics, there was a 12.1% participation of Hispanics with no significant disparity observed (p=1). Conclusions: Lack of representation of minorities persist in post COVID area FDA approved drugs clinical trials in prostate cancer. Lack of a more comprehensive data in race have also been seen in recent trials. Further implementation of policies for better data capture and standardization in the nomenclature of ethnicity should be pursued. Additionally, in international collaboration trials, a separate data on US participants utilizing NCI SEER data ethnicity nomenclature should be considered.

Introduction: Prostate cancer is the second most common cancer among men worldwide. In 2021, it is estimated that 248,530 men in the United States will be diagnosed with prostate cancer, and 34,130 will die from the disease. Although current treatments have success initially, development of resistance commonly leads to recurrence of an incurable castrate-resistant form of the disease. Thus, significant need for novel therapies to improve the outcome of castrate-resistant prostate cancer remains. B7-H3 (CD276), a member of the B7 family of immunomodulatory molecules, is overexpressed in primary and metastatic prostate cancer, and correlates with disease severity and poor clinical outcome. MGC018, a duocarmycin-based B7-H3 antibody-drug conjugate, is currently being evaluated in clinical studies. Here, MGC018 was explored preclinically to assess the potential for targeting B7-H3 in prostate cancer. Methods: Immunohistochemistry studies were performed to define the expression of B7-H3 in prostate cancer tissue microarrays (TMA). In vivo efficacy studies were conducted with human prostate cancer cell line-derived xenograft (CDX) models to explore the antitumor activity of MGC018 as a single agent and in combination with Poly (ADP-ribose) polymerase (PARP) and androgen receptor (AR) inhibitors. Based on the results in the CDX studies, in vivo efficacy studies were extended to a panel of metastatic prostate cancer patient-derived xenograft (PDX) models, which exhibit heterogenous expression of B7-H3 and more closely mimic the biological characteristics of patient tumors. Results: Staining of prostate tumor TMAs revealed high expression of B7-H3 in primary and metastatic prostate cancer. Of the prostate samples evaluated, 95% (38/40) of the tumor samples were positive for B7-H3 (H-score ≥ 20): 65% had H-scores greater than 200, while 20% and 10% had H-scores between 101-200 and 1-100, respectively. MGC018 demonstrated in vitro cytotoxicity toward B7-H3-positive human prostate cancer cell lines. The in vitro cytotoxicity translated to potent antitumor activity in vivo toward prostate cancer CDX models, and the antitumor activity of MGC018 was enhanced when combined with inhibitors of PARP or AR. In PDX models of metastatic prostate cancer, MGC018 was active as a single agent toward heterogeneous B7-H3-expressing tumors, and combining MGC018 with inhibitors of PARP or AR led to a greater response in some models. Conclusion: B7-H3 is frequently overexpressed in prostate cancer. MGC018 demonstrated potent antitumor activity in vivo toward CDX and PDX models of prostate cancer, and enhanced antitumor activity when combined with inhibitors of PARP or AR. These results support prostate cancer as an indication that may be responsive to ADC-based treatments directed toward B7-H3. MGC018 is being investigated in metastatic prostate cancer in a Phase 1/2 clinical study. Citation Format: Juniper A. Scribner, Francine Z. Chen, Anushka De Costa, Ying Li, Michael Chiechi, Thomas Son, Jeff Hooley, Jonathan Li, Scott Koenig, Chet Bohac, Ezio Bonvini, Paul A. Moore, Deryk Loo. Targeting B7-H3 in prostate cancer: Preclinical proof of concept with MGC018, an investigational anti-B7-H3 antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 330.

Although scores of disease-specific cancer organizations nationwide often compete over charitable and government funding in these tough economic times, many also work collaboratively toward common goals. “There's so much data that crosses the border these days that the more we learn about one cancer, there's applicability to other cancers as well,” says Dan Zenka, vice president of communications for the Prostate Cancer Foundation (PCF). Matthew Alsante, executive director of the Sarcoma Foundation ofAmerica (SFA), agrees.” We think you can do more together, and we work with other organizations to advance the cause for all cancers:' Alsante says. “Congress wants to advance cures, and the future of cancer research may be drugs for specific pathways—like the p53 gene that malfunctions in multiple cancers—rather than one cancer versus another.” Although many alliances have been formed among disease-specific organizations, each group also has a specific agenda based on their constituents' unique needs. “CancerScope” spoke with leaders of a few of these groups to learn what they are doing to improve the lives of patients with these diseases. Lung cancer is the leading cause of cancer death in every ethnic group and will kill nearly 160,000 people nationwide in 2010. The 5-year survival rate is approximately 15.8%. Nevertheless, federal funds for research in terms of “dollars per death” are approximately $1,400 for thc disease versus nearly $29,000 for breast cancer and more than $13,000 for prostate cancer, according to statistics gathered by the Lung Cancer Alliance (LCA). The reasons for the lack of funding include both the stigma of smoking associated with the disease and the amount of money that is invested in tobacco cessation programs. “While we support tobacco cessation efforts, we know you can't solve this disease when nearly 80% of new lung cancer patients have either quit or never smoked,” says Kay Cofranccsco, LCA's director of advocacy relations. Lack of research funding has kept scientists from entering the field, whilc at the same time the disease has fewer advocates than other cancers. Recognizing these problems as a political issue, leaders of the organization, which was founded in 1995 in Washington State, relocated to Washington, DC in 2005.Their biggest success to date is securing the Department of Defense's congressionally directed medical research program for lung cancer, which began 2 years ago. The research is specifically directed toward providing early detection and screening options for veterans, who are at higher risk for the disease than the general population. In 2009, the program received $20 million in funding, followed by S 15 million in 2010, according to Cofrancesco. The organization has formed 5 state chapters to raise awareness and increase state funding. They also are actively lobbying for passage of the federal Lung Cancer Mortality Reduction Act, which would authorize the departments of Health and Human Services, Defense, and Veteransbffairs to develop a comprehensive research strategy to significantly reduce lung cancer mortality by 2015, targeting prevention, diagnosis, and treatment.The bill also would provide first-year funding of $75 million for 4 National Institutes of Health (NIH) divisions to expand their lung cancer research programs. Because lung cancer is the leading cancer killer, overall cancer survival ratcs will not be reduced significantly until more money is put into research and early detection, Cofrancesco notes. Meanwhile, the LCA is advocating for more clinical trials to be conducted in this area, just as extensive trials have occurred in determining the effcctivencss of mammography screening for women aged younger than 50 years. In terms of awareness, “I think we're in much better shape than we were 5 years ago,” Cofrancesco says, noting that the deaths of broadcaster Peter Jennings and actress Dana Reeve have brought attention to the importance of research. “It's a testament to the scrappiness and dedication of the survivors who have talked about the disease— and it's been up to us to keep the drumbeat going.” “We look at ourselves as the cog in the wheel to bring new therapies to sarcoma patients,” says Alsante.” The spokes include the NCI [National Cancer Institute], NIH, FDA [Food and Drug Administration], the pharmaceutical industry, academic institutions, and sarcoma patients.” The organization was founded in 2000 by Mark Thornton, MD; his wife, Patricia; and John Brooks, MD, a pathologist. The Thorn- tons' son had sarcoma, and at the time no organizations cxisted to provide support for the disease. Sarcoma has more than 100 different subtypes, occurs in approximately 12,000 patients per year, and constitutes approximately 1% of all adult and 15% of all childhood cancers. Since its inception, the SFA has funded 50 sarcoma research grants and partnered with the American Society of Clinical Oncology ASCO) in funding 4 young investigator awards and 2 advanced clinical research awards. “There is more research going on now than ever in the history of the disease,” notes Alsante. Nevertheless, many challenges remain, including the barriers to developing and gaining approval for new therapies for sarcoma and other rare diseases. The SFA and other rare disease organizations maintain that the FDA has been inconsistent in its approval process for drugs for many rare diseases, creating confusion and a disincentive for the pharmaceutical industry to develop new drugs. Alsantc and others testified at an FDA public hearing on the issue in June. After reviewing testimony, the FDA was slated to develop a guidance document by September 11,2011, to provide more detailed guidelines for developers of drugs for rare diseases. Although the Orphan Drug Act has helped somewhat in developing new drugs, it has been insufficient, Alsante says. “Again and again the FDA has demanded ‘overall survival’ as the primary endpoint for clinical trials in cases when there are not enough patients to ever complete a trial,” he says, noting that the SFA has asked the FDA for a guidance document since 2007. “We're looking for guidance that progression-free survival as an endpoint would be acceptable, which they have approved for multiple drugs.” He cites the example of 2 sarcoma drugs—mifamurtide (Mepact) and trabectedin (Yondelis)—which have been approved for use in Europe but denied approval by the FDA. Recently a company submitted a phase 3 trial idea for drug for 2 extremely rare sarcomas. Although the European Medicines Agency accepted progression-free survival as an endpoint, the FDA did not. As a result, the company decided not to pursue the trial. “When you have maybe 200 people in the world with [a particular sarcoma], in order to get a statistically valid endpoint, you would need 100% participation,” Alsante says.” And tracking overall survival can take years. That's such a disincentive to a company when not many people will even be using the drug.” In the US, the drugs that are available for sarcoma are therapies that were approved 30 years ago for other indications and have trickled through to sarcoma with the hope that they'll be successful, he adds. With 20 chapters nationwide, the SFA has been very successful in raising money and has created a national sarcoma patient registry, which should aid research, Alsante says. Each year, the organization holds a national gala in NewYork City as well as an educational conference for patients and one for professionals as part ofASCO's annual meeting. The fight against prostate cancer includes an effort by 13 organizations that make up the Prostate Cancer Round- table, a group that collaborates to support patients and their families and to find new diagnostics and treatments for a disease that will strike approximately 218,000 men this ycar. Among those in the roundtable are 2 well-known organizations: the PCF, which supports research, and the Us TOO International Prostate Cancer Education and Support Network, which addresses education and awareness. The PCF, founded by Michael Milken in 1993, is the leading philanthropic organization for prostate cancer research, funding more than $400 million in projects since its inccption.That amount encompasses more than 1500 programs at nearly 200 research centers in 20 countries. “We started a new approach called venture philanthropy;' says Zenka, who was recently diagnosed with prostate cancet “We shortened the application to 5 pages, and we reviewed in 60 days and funded in 30. If a project takes a left turn and changes direction, grantecs don't have to reapply—they just have to teli us where their work is taking them and why:' Every ycar,fundcd scientists share their data at a PCF retreat. Despite the economic downturn, the past 2 years have been some of the PFC's best in terms of fundraising, mainly because it is a small organization that has been able to react and adjust more easily than larger organizations, Zenka notes.The organization raises approximately $37 million each year through a variety of programs, with approximately 85% of those funds directly supporting research. Events range from the Home Run Challenge—in which money is pledged for home runs in designated baseball games—to Movcmbcr, a worldwide fundraiser for men's diseases in which men receive pledges for growing mustaches (“Mo” is an Australian term for moustache). “We've seen more progress this year in prostate cancer research than probably in the last decade,” Zenka notes. He points to the discovery of 24 gene fusions related to prostate cancer that create new targets and will help to better direct research toward new, promising personalized medicine efforts. Several of the Prostate Cancer Rouud table organizations worked together to organize an “Advance on Washington” event during the week of September 13, 2010. The groups hope to build awareness and support on a federal level. “We know we spend about $3 billion a year in over treating the disease, yet more than 32,000 men are dying each year—we'd love to see that $3 billion put into research,” Zenka says. Meanwhile, Us TOO is celebrating its 20th anniversary of helping men and their families to make informed decisions about prostate cancer through support, education, and advocacy. The Chicago-based organization founded by 5 prostate cancer survivors now has 325 affiliated support groups and chapters worldwide, primarily in the United States. “Our name comes from the realization that cancer is important for us too—just as breast cancer is important to women,” says Us TOO president and CEO Tom Kirk.” Like the breast cancer movement was 30 years ago when people didn't use the word ‘breast’ in public, we're gaining awareness and have seen a big turnaround in the last 5 to 10 years.” Unlike when the organization first was founded, when there was a lack of information concerning prostate cancer diagnosis and treatment, people who contact Us TOO now are often confused by the overwhelming amount of information available,Kirk notes.The group's main challenges are getting men to speak openly about the disease, to understand the risks, and to take action rather than trying to maintain a heroic attitude that their needs come last. “Doctors now don't have as much time to spend with us as they did in the past, so we need to turn to each other for information, and men need to understand that they have to be the quarterback or CEO of their own health care,” Kirk says. The Leukemia and Lymphoma Society (LLS) is the world's largest voluntary health organization dedicated to funding blood cancer research, education, and patient services. It has 59 chapters across the United States and Canada and raises approximately $275 million each year for leukemia, lymphoma, and myeloma cancers. Since its inception some 61 years ago, it has funded more than $750 million in research, notes CEO John Walter. “Other than extreme exposure to benzene, there are no known causes or opportunities for prevention, so research is very important to us:' Walter says. We're focused on funding cures for these diseases:' Recognizing that pathways to new treatments take time, LLS has chosen to continue a multifaceted approach that also focuses on patients' existing needs. Those include services such as family and peer support groups, a back-to- school program for kids, and direct financial aid to help patients afford their insurance co-pays. In the legislative arena, the organization is focused on ensuring sufficient funding of the Cures Acceleration Network, which was part of the Patient Protection and Affordable Care Act signed into law by President Obama in March 2010.The provision creates a new office within the NIH, under the director's leadership, which is charged with speeding translation of basic scientific discoveries into treatments for patients. The goal is to encourage partnerships within the NIH, the pharmaceutical industry, academia, and other organizations to develop new collaborations in this area. LLS already has such a program on a smaller scale, in which they mine work from their academic scientists to generate clinical trials. One example is work by a Canadian researcher that led to development of a promising treatment for acute myeloid leukemia, which has a poor outcome and few new treatments. LLS partnered with Princess Margaret Hospital in Toronto, Ontario, Canada, and the University of Kansas in Lawrence to support the project, and within 9 months helped launch a phase 1 clinical trial for the compound. The organization also canvases the biotech industry to determine who might have compounds that could be translated into clinical trials. Because the blood cancer patient population is relatively small (an estimated 137,260 people will be diagnosed in 2010) the opportunity for profit is not large. That why LLS funding combined with federal government support of new treatments is vital, Walter notes. The organization is primarily funding phase 1 trials, with the hope that promising results will encourage partnerships with companies that can advance the research and eventually bring a drug to market. “In 3 to 5 years, one of these treatments will be successful, and we'll have a new standard of for our patients in the near tcrm” Walter says.

The prognosis in the setting of metastatic castration-resistant prostate cancer patients (mCRPC) remains limited. Therefore, novel treatment strategies remain an unmet need. Antibody-drug conjugates (ADC) emerged as a new drug concept with the potential to deliver a cytotoxic payload with limited off-target toxicity and potentially bystander effect. Following the success of ADCs in breast cancer and urothelial tumours, their activity in prostate cancer is now under investigation. Thus, the aim of this systematic review was to identify published and ongoing prospective clinical trials regarding ADC treatment in prostate cancer.A systematic search of PubMed, MEDLINE, and Web of Science was conducted as per PRISMA guidelines to identify prospective clinical trials of ADCin prostate cancer. Trials are currently ongoing on ClinicalTrials.gov and in the EU. The Clinical Trials Register was also identified. s, publications in languages other than English, review articles, retrospective analyses, and phase I trials were excluded.A total of six phase I/II prospective clinical trials already published were included. Seven ongoing trials were also identified. All studies were in the refractory/advanced tumour setting, and two included only mCRPC patients. The ADC targets were prostate-specific membrane antigen (PSMA), trophoblast cell surface antigen-2 (TROP-2), six-transmembrane epithelial antigen of prostate-1 (STEAP-1), tissue factor (TF), delta-like protein 3 (DLL-3), B7-H3 family of proteins (B7-H3), and human epidermal growth factor receptor 2 (HER2). Regarding the efficacy of PSMA ADC treatment in the second-line or beyond mCRPC setting, a PSA ≥ 50% decline rate in 14% of all treated patients was reported. One patient achieved a complete response with TROP-2 ADC. Overall, a wide range of safety issues were raised, particularly in connection with neuropathy and hematologic toxicity.Novel therapies have been changing the scope of treatment in mCRPC. ADCs seem to provide efficacy benefits, even with potential toxicity. The results of most prospective ongoing studies are still awaited, and a longer follow-up time is warranted to evaluate the real impact of ADCs in PCa.

Antibody-Drug Conjugates in urothelial, prostate, and renal cell cancers: A review of current and emerging therapies.

In the mid-1980’s, after it was found that patients rapidly developed neutralising antibodies to tumour-directed ‘therapeutic mouse antibodies’, the concept of using these mouse antibodies to deliver cytotoxic therapeutics emerged. However, success was limited. Anti-mouse antibodies developed even with a limited number of infusions of the antibody-drug conjugates, and often the cytotoxic agents were released in the blood stream producing serious toxicities. The field of antibody-conjugates was quiet while technology for humanisation of mouse antibodies and the means of producing fully human antibodies evolved, and linker chemistry was developed, which allowed stable transport of antibody-conjugates to the target cells and release of the cytotoxic agent inside the target cells (Fig. 4.1) [1–3]. The first antibody-drug conjugate to reach Food and Drug Administration (FDA) approval in 2000 was gemtuzumab ozogamicin (Mylotarg), which targeted CD33 on the surface of acute myeloid leukaemia cells and delivered the potent cytotoxic agent, calicheamicin, inside the leukaemia cells. In 2010, gemtuzumab ozogamicin was withdrawn from the market after failing to produce sufficient efficacy in follow-up clinical trials [4]. Two antibody-drug conjugates (ADCs), trastuzumab emtansine (T-DM1; Kadcyla) and brentuximab vedotin (SGN-35; Adcetris) reached FDA approval in 2014 and 2011 for treatment of metastatic breast cancer and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively [5, 6]. Approximately 50 ADCs have reached clinical trial to date, with more than 40 in trials currently and nearly 20 in, or having completed Phase 2 clinical trials (Table 4.1). The ADCs under investigation target haematological and solid tumours [7, 8]. The current chapter focuses on those that may be useful in the treatment of GI cancers.